Dosing regimen

ABSTRACT

This invention relates to a method of treatment and dosing regimen for treating mammalian tumors by the discontinuous administration of a farnesyl transferase inhibitor over an abbreviated one to five day dosing schedule.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application under 35 USC 371 ofPCT/EP01/01937 filed Feb. 20, 2001, which claims priority from U.S.Provisional Patent Application Ser. No. 60/184,551, filed Feb. 24, 2000.

FIELD OF THE INVENTION

The present invention relates to a method for treating mammalian tumorsby the administration of a farnesyl protein transferase (FPT) inhibitorusing an intermittent dosing schedule. The regimen involves theadministration of a FPT inhibitor over an abbreviated one to five daydosing schedule whereby anticancer effects are achieved which continuebeyond the period of administration.

BACKGROUND OF THE INVENTION

Over the last decade cancer research has identified specific geneticlesions which induce malignant transformation and drive tumor growth. Itis now recognized that mutations, deletions or alterations in theexpression of normal mammalian genes involved in growth control convertsthese “protooncogenes” into “oncogenes”. The ras family of oncogenesconsisting of H-ras, K-ras and N-ras oncogenes encode a highly conservedGTP-binding protein or Mr=21,000 (p21).

Oncogenes frequently encode components of signal transduction pathwayswhich lead to stimulation of cell growth and mitogenesis. Oncogeneexpression in cultured cells leads to cellullar transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer. In order toacquire transforming potential the precursor of the ras oncoprotein mustundergo farnesylation of the cysteine residue located in acarboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzesthis modification, farnesyl protein tranferase, have therefore beensuggested as anticancer agents for tumors in which ras contributes totransformation. Mutated oncogenic forms of ras are frequently found inmany human cancers, most notably in more than 50% of colon andpancreatic carcinomas (Kohl et al., Science, vol. 260, 1384 to 1837,1993).

The protein products of the ras ocogenes have been the focus of oncologydrug discovery efforts because of some unique features of the cellularmetabolism of these proteins. To function in signal transduction andcell transformation, ras must attach to the plasma membrane to promoteinteractions with membrane localization also SH2/SH3 domain adaptorproteins Grb2 and SOS. Ras membrane localization also functions in theactivation of downstream effectors such as Raf protein kinase. Newlysynthesized Ras proteins must pe posttranslationally modified inmammalian cells by farnesylation followed by the proteolytiac cleavageof the three terminal amino acids and carboxy-O-methylation to producethe hydrophobicity or recognition sites which allow proper membranelocalization. The initial and rate-limiting post-translationalmodification of Ras involves the covalent attachment of farnesol via athioether linkage to a single cysteine residue positioned four aminoacids from the carboxy terminus of the protein. This reaction iscatalyzed by farnesyl protein transferase (FPT). The enzyme requiresonly the four C-terminal amino acids or CAAX motif for specific bindingand catalysis of protein substrates.

Farnesyl protein transferase inhibitors have been described as beinguseful in the treatment of mammalian cancers and in particular in thetreatment of colon and pancreatic cancers.

WO-97/21701, and it's United States counterpart, U.S. Pat. No.6,037,350, describe the preparation, formulation and pharmaceuticalproperties of farnesyl protein transferase inhibiting(imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II)and (III), as well as intermediates of formula (II) and (III) that aremetablolized in vivo to the compounds of formula (I). The compounds offormulas (I), (II) and (III) are represented by

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein

-   -   the dotted line represents an optional bond;    -   X is oxygen or sulfur;    -   R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,        quinolinylC₁₋₆alkyl, pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,        aminoC₁₋₆alkyl,        -   or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)-R⁹ or            —Alk¹—S(O)₂—R⁹, wherein Alk¹ is C₁₋₆alkanediyl,            -   R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino,                C₁₋₈alkylamino or C₁₋₈alkylamino substituted with                C₁₋₆alkyloxycarbonyl;    -   R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo,        cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,        C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyl-oxy, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,        Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,        4,4-dimethyloxazolyl; or        -   when on adjacent positions R² and R³ taken together may form            a bivalent radical of formula            —O—CH₂—O—  (a-1)            —O—CH₂—CH₂—O—  (a-2)            —O—CH═CH—  (a-3)            —O—CH₂—CH₂—  (a-4)            —O—CH₂—CH₂—CH₂—  (a-5) or            —CH═CH—CH═CH—  (a-6)    -   R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy,        C₁₋₆alkylthio, amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;    -   R⁶ and R⁷ each independently are hydrogen, halo, cyano,        C₁₋₆alkyl, C ₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio,        di(C₁₋₆alkyl)amino, or        -   when on adjacent positions R⁶ and R⁷ taken together may form            a bivalent radical of formula            —O—CH₂—O—  (c-1) or            —CH═CH—CH═CH—  (c-2)    -   R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,        cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl,        hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or        di(C₁₋₆alkyl)-aminoC₁₋₆alkyl, imidazolyl, haloC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or a radical of        formula        —O—R¹⁰  (b-1)        —S—R¹⁰  (b-2)        —N—R¹¹R¹²  (b-3)    -   wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,        Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl-C₁₋₆alkyl, or a radical or        formula —Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;    -   R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;    -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl,        C₁₋₆alkylcarbonyl-C₁₋₆alkyl, a natural amino acid, Ar¹carbonyl,        Ar²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,        C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy,        aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,        C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical or formula        —Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;    -   wherein Alk² is C₁₋₆alkanediyl;        -   R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,            hydroxy-C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;        -   R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;        -   R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or            Ar²C₁₋₆alkyl;    -   R¹⁷ is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,        Ar¹;    -   R¹⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;    -   R¹⁹ is hydrogen or C₁₋₆alkyl;    -   Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,        amino, C₁₋₆alkyloxy or halo; and    -   Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,        amino, C₁₋₆alkyloxy or halo.

WO-97/16443, and it's United States counterpart, U.S. Pat. No.5,968,952, concern the preparation, formulation and pharmaceuticalproperties of farnesyl protein transferase inhibiting compounds offormula (IV), as well as intermediates of formula (V) and (VI) that aremetabolized in vivo to the compounds of formula (IV). The compounds offormulas (IV), (V) and (VI) are represented by

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein

-   -   the dotted line represents an optional bond;    -   X is oxygen or sulfur;    -   R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,        quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl,        aminoC₁₋₆alkyl,        -   or a radical of formula -—Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or            —Alk¹—S(O)₂—R⁹,        -   wherein Alk¹ is C₁₋₆alkanediyl,            -   R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino,                C₁₋₈alkylamino or C₁₋₈alkylamino substituted with                C₁₋₆alkyloxycarbonyl;    -   R² and R³ each independently are hydrogen, hydroxy, halo, cyano,        C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,        C₁₋₆alkyloxyC₁₋₆alkyloxy, amino-C₁₋₆alkyloxy, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,        Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        trihalomethyl, trihalomethoxy, C₂₋₆alkenyl; or        -   when on adjacent positions R² and R³ taken together may form            a bivalent radical of formula            —O—CH₂—O—  (a-1)            —O—CH₂—CH₂—O—  (a-2)            —O—CH═CH—  (a-3)             —O—CH₂—CH₂—  (a-4)            —O—CH₂—CH₂—CH₂—  (a-5)            or            —CH═CH—CH═CH—  (a-6)    -   R⁴ and R⁵ each independently are hydrogen, Art, C₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl or        C₁₋₆alkylS(O)₂C₁₋₆alkyl;    -   R⁶ and R⁷ each independently are hydrogen, halo, cyano,        C₁₋₆alkyl, C₁₋₆alkyloxy or Ar²oxy;    -   R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl-carbonylC₁₋₆alkyl,        cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,        hydroxy-carbonylC₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,        mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl, haloC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, Ar¹,        Ar²C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl;    -   R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;    -   R¹¹ is hydrogen or C₁₋₆alkyl;    -   Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,        amino, C₁₋₆alkyloxy or halo;    -   Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,        amino, C₁₋₆alkyloxy or halo.

WO-98/40383, and it's United States counterpart, U.S. Pat. No.6,187,786, concern the preparation, formulation and pharmaceuticalproperties of farnesyl protein transferase inhibiting compounds offormula (VII)

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

-   -   the dotted line represents an optional bond;    -   X is oxygen or sulfur;    -   —A— is a bivalent radical of formula

—CH═CH— (a-1), —CH₂—S— (a-6), —CH₂—CH₂— (a-2), —CH₂—CH₂—S— (a-7),—CH₂—CH₂—CH₂— (a-3), —CH═N— (a-8), —CH₂—O— (a-4), —N═N— (a-9), or—CH₂—CH₂—O— (a-5), —CO—NH— (a-10);

-   -   wherein optionally one hydrogen atom may be replaced by        C₁₋₄alkyl or Ar¹;

R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar²,Ar²-C₁₋₆alkyl, Ar²-oxy, Ar²—C₁₋₆alkyloxy; or when on adjacent positionsR¹ and R² taken together may form a bivalent radical of formula—O—CH₂—O—  (b-1)—O—CH₂—CH₂—O—  (b-2)—O—CH═CH—  (b-3)—O—CH₂—CH₂—  (b-4)—O—CH₂—CH₂—CH₂—  (b-5)or—CH═CH—CH═CH—  (b-6)

R³ and R⁴ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar³-oxy, C₋₆alkylthio, di(C₁₋₆alkyl) amino, trihalomethyl,trihalomethoxy, or when on adjacent positions R³ and R⁴ taken togethermay form a bivalent radical of formula—O—CH₂—O—  (c-1)—O—CH₂—CH₂—O—  (c-2)or—CH═CH—CH═CH—  (c-3)

R⁵ is a radical of formula

-   -   wherein R¹³ is hydrogen, halo, Ar⁴, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxy-C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,        C₁₋₆alkyloxy-carbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl or        C₁₋₆alkylS(O)₂C₁₋₆alkyl;    -   R¹⁴is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;

R⁶ is hydrogen, hydroxy, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar⁵,Ar⁵—C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula—O—R⁷  (e-1)—S—R⁷  (e-2)—N—R⁸R⁹  (e-3)

-   -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar⁶,        Ar⁶—C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of        formula —Alk—OR¹⁰ or —Alk—NR¹¹R¹²;        -   R⁸ is hydrogen, C₁₋₆alkyl, Ar⁷ or Ar⁷—C₁₋₆alkyl;        -   R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,            C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar⁸,            Ar⁸—C₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl, Ar⁸-carbonyl,            Ar⁸-C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,            C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy,            aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,            C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino,            -   or a radical or formula —Alk—OR¹⁰ or —Alk—NR¹¹R¹²;    -   wherein Alk is C₁₋₆alkanediyl;        -   R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,            hydroxy-C₁₋₆alkyl, Ar⁹ or Ar⁹—C₁₋₆alkyl;        -   R¹¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹⁰ or            Ar¹⁰—C₁₋₆alkyl;        -   R ¹² is hydrogen, C₁₋₆alkyl, Ar¹¹ or Ar¹¹—C₁₋₆alkyl; and    -   Ar¹ to Ar¹¹ are each independently selected from phenyl; or        phenyl substituted with halo, C₁₋₆alkyl, C₁₋₆alkyloxy or        trifluoromethyl.

WO-98/49157 and it's United States counterpart, U.S. Pat. No. 6,177,432,concern the preparation, formulation and pharmaceutical properties offarnesyl protein transferase inhibiting compounds of formula (VIII).

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

-   -   the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹ and R² each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar¹C₁₋₆alkyl, Ar¹oxy or Ar¹C₁₋₆alkyloxy;

R³ and R⁴ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar¹oxy, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, trihalomethylor trihalomethoxy;

R⁵ is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, Ar¹,Ar¹C₁₋₆alkyloxyC₁₋₆alkyl; or a radical of formula—O—R¹⁰  (a-1)—S—R¹⁰  (a-2)—N—R¹¹R¹²  (a-3)

-   -   wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,        Ar¹C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of        formula —Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;        -   R¹¹ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;        -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,            C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹,            Ar¹C₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl, Ar¹carbonyl,            Ar¹C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,            C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy,            aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,            C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino,        -   or a radical or formula —Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;        -   wherein Alk is C₁₋₆alkanediyl;            -   R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,                hydroxy-C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;            -   R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;            -   R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or                Ar¹C₁₋₆alkyl;

R⁶ is a radical of formula

-   -   wherein R¹⁶is hydrogen, halo, Ar¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxy-C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthioC₁₋₆alkyl,        C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;        -   R¹⁷is hydrogen, C₁₋₆alkyl or di(C₁₋₄alkyl)aminosulfonyl;

R⁷ is hydrogen or C₁₋₆alkyl provided that the dotted line does notrepresent a bond;

R⁸ is hydrogen, C₁₋₆alkyl or Ar²CH₂ or Het¹CH₂;

R⁹ is hydrogen, C₁₋₆alkyl , C₁₋₆alkyloxy or halo; or

R⁸ and R⁹ taken together to form a bivalent radical of formula—CH═CH—  (c-1)—CH₂—CH₂—  (c-2)—CH₂—CH₂—CH₂—  (c-3)—CH₂—O—  (c-4)or—CH₂—CH₂—O—  (c-5)

Ar¹ is phenyl; or phenyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl;

Ar² is phenyl; or phenyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl; and

Het¹ is pyridinyl; pyridinyl substituted with 1 or 2 substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl.

WO-00/39082, and it's United States counterpart, U.S. patent applicationSer. No. 09/868,992, flied Aug. 29, 2001, concern the preparation,formulation and pharmaceutical properties of farnesyl proteintransferase inhibiting compounds of formula (IX)

or the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

-   -   ═X¹—X²—X³— is a trivalent radical of formula

═N—CR⁶═CR⁷— (x-1), ═CR⁶—CR⁷═CR⁸— (x-6), ═N—N═CR⁶— (x-2), ═CR⁶—N═CR⁷—(x-7), ═N—NH—C(═O)— (x-3), ═CR⁶—NH—C(═O)— (x-8), or ═N—N═N— (x-4),═CR⁶—N═N— (x-9); ═N—CR⁶═N— (x-5),

-   -   wherein each R⁶, R⁷ and R⁸ are independently hydrogen,        C₁₋₄alkyl, hydroxy, C₁₋₄alkyloxy, aryloxy, C₁₋₄alkyloxycarbonyl,        hydroxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl, mono- or        di(C₁₋₄alkyl)aminoC₁₋₄alkyl, cyano, amino, thio, C₁₋₄alkylthio,        arylthio or aryl;

>Y¹-Y² is a trivalent radical of formula>CH—CHR⁹—  (y-1)>C═N—  (y-2)>CH—NR⁹—  (y-3)or>C═CR⁹—  (y-4)

-   -   wherein each R⁹ independently is hydrogen, halo, halocarbonyl,        aminocarbonyl, hydroxyC₁₋₄alkyl, cyano, carboxyl, C₁₋₄alkyl,        C₁₋₄alkyloxy, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, mono-        or di(C₁₋₄alkyl)amino, mono- or di(C¹⁻⁴alkyl)aminoC₁₋₄alkyl,        aryl;    -   r and s are each independently 0, 1, 2, 3, 4 or 5;    -   t is 0, 1, 2 or 3;    -   each R¹ and R² are independently hydroxy, halo, cyano,        C₁₋₆alkyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,        C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkylthio,        C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,        aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)amino, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, aryl, arylC₁₋₆alkyl, aryloxy or        arylC₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        aminocarbonyl, aminoC₁₋₆alkyl, mono- or        di(C₁₋₆alkyl)aminocarbonyl, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyl; or    -   two R¹ or R² substituents adjacent to one another on the phenyl        ring may independently form together a bivalent radical of        formula        —O—CH₂—O—  (a-1)        —O—CH₂—CH₂—O—  (a-2)        —O═CH═CH—  (a-3)        —O—CH₂—CH₂—  (a-4)        —O—CH₂—CH₂—CH₂—  (a-5)        or        —CH═CH—CH═CH—  (a-6)

R³ is hydrogen, halo, C₁₋₆alkyl, cyano, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkylthioC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, hydroxycarbonyl,hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, C ₁₋₆alkyloxycarbonyl, aryl,arylC₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl;

-   -   or a radical of formula        —O—R¹⁰  (b-1)        —S—R¹⁰  (b-2)        —NR¹¹R¹²  (b-3)    -   wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, aryl,        arylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical of        formula —Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;        -   R¹¹ is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl;        -   R¹² is hydrogen, C₁₋₆alkyl, aryl, hydroxy, amino,            C₁₋₆alkyloxy, C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl,            C₁₋₆alkylcarbonylamino, mono- or di(C₁₋₆alkyl)amino,            C₁₋₆alkylcarbonyl, aminocarbonyl, arylcarbonyl,            haloC₁₋₆alkylcarbonyl, arylC₁₋₆alkylcarbonyl,        -   C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, mono-            or di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may            optionally be substituted by one or more substituents            independently selected from aryl or C₁₋₃alkyloxycarbonyl,            aminocarbonylcarbonyl, mono- or            di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical or formula            —Alk—OR¹³ or —Alk—NR¹⁴R¹⁵;    -   wherein Alk is C₁₋₆alkanediyl;        -   R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,            hydroxyC₁₋₆alkyl, aryl or arylC₁₋₆alkyl;        -   R¹⁴ is hydrogen, C₁₋₆alkyl, aryl or arylC₁₋₆alkyl;        -   R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, aryl or            arylC₁₋₆alkyl;    -   R⁴ is a radical of formula    -   wherein R¹⁶ is hydrogen, halo, aryl, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, C₁₋₆aikyloxyC₁₋₆alkyl, C₁₋₆alkyloxy,        C₁₋₆alkylthio, amino, mono- or di(C₁₋₄alkyl)amino,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthioC₁₋₆alkyl,        C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;        -   R¹⁶ may also be bound to one of the nitrogen atoms in the            imidazole ring of formula (c-1) or (c-2), in which case the            meaning of R¹⁶ when bound to the nitrogen is limited to            hydrogen, aryl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,            C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,            C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;        -   R¹⁷ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,            arylC₁₋₆alkyl, trifluoromethyl or            di(C₁₋₄alkyl)aminosulfonyl;

R⁵ is C₁₋₆alkyl , C₁₋₆alkyloxy or halo;

-   -   aryl is phenyl, naphthalenyl or phenyl substituted with 1 or        more substituents each independently selected from halo,        C₁₋₆alkyl, C₁₋₆alkyloxy or trifluoromethyl.

Other useful farnesyl protein transferase inhibitors include Arglabin(i.e.1(R)-10-epoxy-5(S),7(S)-guaia-3(4),11(13)-dien-6,12-olide descibedin WO-98/28303 (NuOncology Labs); perrilyl alcohol described inWO-99/45912 (Wisconsin Genetics); SCH-66336, i.e.(+)-(R)-4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide,described in U.S. Pat. No. 5874442 (Schering); L778123, i.e.1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,described in WO-00/01691 (Merck); compound2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone described in WO-94/10138 (Merck); and BMS 214662, i.e.(R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulphonyl)-1H-1,4-benzodiazapine-7-carbonitrile,described in WO 97/30992 (Bristol Myers Squibb) and Pfizer compounds (A)and (B) described in WO-00/12498 and WO-00/12499:

The compounds are generally described as being inhibitors of farnesylprotein transferase useful in the treatment of mammalian tumors.Generally in the treatment of cancerous tumors about 0.01 mg/kg to 100mg/kg body weight of a farnesyl protein transferase inhibitor isadministered at doses of about two, three, four or more sub doses atappropriate intervals throughout the day. This dosing schedule ispredicated on the hypothesis that continuous exposure to the activecompound and resultant inhibition of FPT were required in order tomaintain antitumor effects.

Unexpectedly, it has been found that an interrupted dosing regimen ofabout five days containing a farnesyl protein transferase inhibitor asthe active ingredient followed by about two weeks without treatmentresults in suppression of mammalian tumor growth.

It is an object of the present invention to provide a method oftreatment and a dosing regimen comprising a discontinuous dosingschedule in which a farnesyl protein transferase inhibitor isadministered to suppress mammalian tumor growth. The regimen comprisesthe administration of a single dose of a farnesyl protein transferaseinhibitor over a one to five day period followed by at least two weekswithout treatment.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating mammalian tumorswhich comprises administering a single dose of a farnesyl proteintransferase inhibitor over a one to five day period. The invention alsorelates to an antitumor dosage regimen in which suppression of tumorgrowth is achieved by the administration of a farnesyl proteintransferase inhibitor over a one to five day period followed by at leasttwo weeks without treatment. The transient one to five day exposure ofmammalian tumors to a farnesyl protein transferase inhibitor producessustained antitumor effects. The inhibition of FPT by a FPT inhibitorunder the method and regimen of the present invention produces lastingalterations in the malignant process which recover only very slowly.

DETAILED DESCRIPTION OF THE INVENTION

Inhibitors of farnesyl transferase (FPT) are known to be useful in thetreatment of mammalian tumors and in particular colon and pancreaticcarcinomas. In previous studies farnesyl protein transferase inhibitorshave been shown to inhibit the growth of mammalian tumors whenadministered as a twice daily dosing schedule. It has been unexpectedlybeen found that administration of a farnesyl protein transferaseinhibitor in a single dose daily for one to five days produced a markedsuppression of tumor growth lasting out to at least 21 days. Inparticular, administration of a farnesyl protein transferase inhibitorat a single dose between 50-1200 mg/kg body weight once daily for one tofive consecutive days after tumor formation produces a markedsuppression of tumor growth lasting out to 21 or more days. The effectis equivalent to administering a farnesyl protein transferase inhibitorcontinuously at a daily 50 mg/kg-100 mg/kg dose in the same tumor model.Upon the appearance of growth in tumors treated according to the methodand/or regimen of this invention, rechallenge with the FPT inhibitor atday 21 produced growth arrest indicating that tumor growth did notemerge from resistant tumor cells. Suppression of tumor growth wasdose-related at doses from 50-1200 mg/kg body weight with the five daysingle dosing schedule. The preferred dosage range is 50-400 mg/kg with200 mg/kg being the most preferred dose. In man based on early Phase 1data, the preferred dose range of 200 to 2400 mg can be expected. Thefinding that a persistent suppression of tumor growth can be obtainedwith only one to five days of treatment with a farnesyl proteintransferase inhibitor was unexpected since it has been assumed thatfarnesyl protein transferase inhibitors as a class would require chroniccontinuous exposure in order to maintain uninterrupted inhibition ofprotein farnesylation.

Examples of FTI inhibitors which may be employed in accordance with thepresent invention include compounds of formula (I), (II), (III), (IV),(V), (VI), (VII), (VIII) or (IX) above, more particularly compounds offormula (I), (II) or (III):

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein

-   -   the dotted line represents an optional bond;    -   X is oxygen or sulfur;    -   R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl,        quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)-aminoC₁₋₆alkyl,        aminoC₁₋₆alkyl,        -   or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or            —Alk¹—S(O)₂—R⁹,        -   wherein Alk¹ is C₁₋₆alkanediyl,            -   R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino,                C₁₋₈alkylamino or                -   C₁₋₈alkylamino substituted with                    C₁₋₆alkyloxycarbonyl;    -   R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo,        cyano, C₁₋₆alky, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,        C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹, Ar²C₁₋₆alkyl, Ar²oxy,        Ar²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,        4,4-dimethyloxazolyl; or        -   when on adjacent positions R² and R³ taken together may form            a bivalent radical of formula            —O—CH₂—O—  (a-1)            —O—CH₂—CH₂—O—  (a-2)            —O—CH═CH—  (a-3)            —O—CH₂—CH₂—  (a-4)            —O—CH₂—CH₂—CH₂—  (a-5)            or            —CH═CH—CH═CH—  (a-6)    -   R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy,        C₁₋₆alkylthio, amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl;    -   R⁶ and R⁷ each independently are hydrogen, halo, cyano,        C₁₋₆alkyl, C₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio,        di(C₁₋₆alkyl)amino, or when on adjacent positions R⁶ and R⁷        taken together may form a bivalent radical of formula        —O—CH₂—O—  (c-1        or        —CH═CH—CH═CH—  (c-2)    -   R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,        cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl,        hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or        di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl, haloC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or a radical of        formula        —O—R¹⁰  (b-1)        —S—R¹⁰  (b-2)        —N—R¹¹R¹²  (b-3)    -   wherein R¹⁰is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,        Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical or        formula —Alk²—OR¹³ or —Alk²-NR¹⁴R¹⁵;        -   R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;        -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,            C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹,            Ar²C₁₋₆alkyl, C₁₋₆alkylcarbonyl-C₁₋₆alkyl, a natural amino            acid, Ar¹carbonyl, Ar²C₁₋₆alkylcarbonyl,            aminocarbonylcarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl,            hydroxy, C₁₋₆alkyloxy, aminocarbonyl,            di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonylamino, C₁₋₆alkylamino,            C₁₋₆alkylcarbonylamino, or a radical or formula —Alk²—OR¹³            or —Alk²—NR¹⁴R¹⁵;            -   wherein Alk² is C₁₋₆alkanediyl;                -   R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,                    hydroxy-C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;                -   R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;                -   R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹                    or Ar²C₁₋₆alkyl;    -   R¹⁷is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,        Ar¹;    -   R¹⁸is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;    -   R¹⁹ is hydrogen or C₁₋₆alkyl;    -   Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,        amino, C₁₋₆alkyloxy or halo; and    -   Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy,        amino, C₁₋₆alkyloxy or halo.

In Formulas (I), (II) and (III), R⁴ or R⁵ may also be bound to one ofthe nitrogen atoms in the imidazole ring. In that case the hydrogen onthe nitrogen is replaced by R⁴ or R⁵ and the meaning of R⁴ and R⁵ whenbound to the nitrogen is limited to hydrogen, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylS(O)C₁₋₆alkyl, C₁₋₆alkylS(O)₂C₁₋₆alkyl.

Preferably the substituent R¹⁸ is situated on the 5 or 7 position of thequinolinone moiety and substituent R¹⁹ is situated on the 8 positionwhen R¹⁸ is on the 7-position.

Interesting compounds are these compounds of formula (I) wherein X isoxygen.

Also interesting compounds are these compounds of formula (I) whereinthe dotted line represents a bond, so as to form a double bond.

Another group of interesting compounds are those compounds of formula(I) wherein R¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹,wherein Alk¹ is methylene and R⁹ is C₁₋₈alkyl-amino substituted withC₁₋₆alkyloxycarbonyl.

Still another group of interesting compounds are those compounds offormula (I) wherein R³ is hydrogen or halo; and R² is halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy or hydroxyC₁₋₆alkyloxy.

A further group of interesting compounds are those compounds of formula(I) wherein R² and R³ are on adjacent positions and taken together toform a bivalent radical of formula (a-1), (a-2) or (a-3).

A still further group of interesting compounds are those compounds offormula (I) wherein R⁵ is hydrogen and R⁴ is hydrogen or C₁₋₆alkyl.

Yet another group of interesting compounds are those compounds offormula (I) wherein R⁷ is hydrogen; and R⁶ is C₁₋₆alkyl or halo,preferably chloro, especially 4-chloro.

A particular group of compounds are those compounds of formula (I)wherein R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxy-carbonylC₁₋₆alkyl, imidazolyl, or a radicalof formula NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is hydrogen or C₁₋₆alkyl.

Preferred compounds are those compounds wherein R¹ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or aradical of formula —Alk^(1—-C(═O)—R) ⁹, wherein Alk¹ is methylene and R⁹is C₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl; R² is halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy,hydroxyC₁₋₆alkyloxy or Ar¹; R³ is hydrogen; R⁴ is methyl bound to thenitrogen in 3-position of the imidazole; R⁵ is hydrogen; R⁶ is chloro;R⁷ is hydrogen; R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,imidazolyl, or a radical of formula —NR¹¹R¹² wherein R¹¹ is hydrogen orC₁₋₁₂alkyl and R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is C₁₋₆alkyl; R¹⁷ is hydrogen and R¹⁸ is hydrogen.

Most preferred compounds are

-   -   4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,        6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;    -   6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;    -   6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone        monohydrochloride.monohydrate;    -   6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,        6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone;        a stereoisomeric form thereof or a pharmaceutically acceptable        acid or base addition salt; and    -   (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone        (Compound 75 in Table 1 of the Experimental part of        WO-97/21701); or a pharmaceutically acceptable acid addition        salt thereof. The latter compound is especially preferred.

Further preferred embodiments of the present invention include compoundsof formula (IX) wherein one or more of the following restrictions apply:

-   -   ═X¹—X²—X³ is a trivalent radical of formula (x-1), (x-2), (x-3),        (x-4) or (x-9) wherein each R⁶ independently is hydrogen,        C₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, amino or aryl and R⁷ is        hydrogen;    -   >y1-y2- is a trivalent radical of formula (y-1), (y-2), (y-3),        or (y-4) wherein each R⁹ independently is hydrogen, halo,        carboxyl, C₁₋₄alkyl or C₁₋₄alkyloxycarbonyl;    -   r is 0, 1 or 2;    -   s is 0 or 1;    -   t is 0;    -   R¹ is halo, C₁₋₆alkyl or two R¹ substituents ortho to one        another on the phenyl ring may independently form together a        bivalent radical of formula (a-1);    -   R² is halo;    -   R³ is halo or a radical of formula (b-1) or (b-3) wherein        -   R¹⁰ is hydrogen or a radical of formula —Alk—OR¹³.        -   R¹¹ is hydrogen;    -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy,        C₁₋₆alkyloxy or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl;        -   Alk is C₁₋₆alkanediyl and R¹³ is hydrogen;    -   R⁴ is a radical of formula (c-1) or (c-2) wherein        -   R¹⁶ is hydrogen, halo or mono- or di(C₁₋₄alkyl)amino;        -   R¹⁷ is hydrogen or C₁₋₆alkyl;    -   aryl is phenyl.

A particular group of compounds consists of those compounds of formula(IX) wherein ═2 X¹-X²-X³ is a trivalent radical of formula (x-1), (x-2),(x-3), (x-4) or (x-9), >Y1-Y2 is a trivalent radical of formula (y-2),(y-3) or (y-4), r is 0 or 1, s is 1, t is 0, R¹ is halo, C₁₋₄)alkyl orforms a bivalent radical of formula (a-1), R² is halo or C₁₋₄alkyl, R³is hydrogen or a radical of formula (b-1) or (b-3), R⁴ is a radical offormula (c-1) or (c-2), R⁶ is hydrogen, C₁₋₄alkyl or phenyl, R⁷ ishydrogen, R⁹ is hydrogen or C₁₋₄alkyl, R¹⁰ is hydrogen or —Alk—OR¹³, R¹¹is hydrogen and R¹² is hydrogen or C₁₋₆alkylcarbonyl and R¹³ ishydrogen;

Preferred compounds are those compounds of formula (IX) wherein═X¹-X²-X³ is a trivalent radical of formula (x-1) or (x-4), >Y1-Y2 is atrivalent radical of formula (y-4), r is 0 or 1, s is 1, t is 0, R¹ ishalo, preferably chloro and most preferably 3-chloro, R² is halo,preferably 4-chloro or 4-fluoro, R³ is hydrogen or a radical of formula(b-1) or (b-3), R⁴ is a radical of formula (c-1) or (c-2), R⁶ ishydrogen, R⁷ is hydrogen, R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ ishydrogen and R¹² is hydrogen;

Other preferred compounds are those compounds of formula (IX) wherein-X¹-X²-X³ is a trivalent radical of formula (x-2), (x-3) or(x-4), >Y1-Y2 is a trivalent radical of formula (y-2), (y-3) or (y-4), rand s are 1, t is 0, R¹ is halo, preferably chloro, and most preferably3-chloro or R¹ is C₁₋₄alkyl, preferably 3-methyl, R² is halo, preferablychloro, and most preferably 4-chloro, R³ is a radical of formula (b-1)or (b-3), R⁴ is a radical of formula (c-2), R⁶ is C₁₄alkyl, R⁹ ishydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² is hydrogen or hydroxy.

The most preferred compounds of formula (IX) are

-   -   7-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinoline;        α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-phenylimidazo,[1,2-a]quinoline-7-methanol;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(        1-methyl-1H-imidazol-5-yl)-imidazo[1,2-a-]quinoline-7-methanol;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-a-]quinoline-7-methanamine;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-1-methyl-α-1-methyl-1H-imidazol-5-yl)-1,2,4-triazolo[4,3-a]quinoline-7-methanol;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine;    -   5-(3-chlorophenyl)-α-(4-chlorophenyl)-N-hydroxy-α-(1-methyl-1H-imidazol-5-yl)tetrahydro[1,5-a]quinoline-7-methanamine;    -   α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo        [1,5-a]quinoline-7-methanamine; the pharmaceutically acceptable        acid addition salts and the stereochemically isomeric forms        thereof.

5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine,especially the (-) enantiomer, and its pharmaceutically acceptable acidaddition salts are especially preferred.

As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; C₁₋₆alkyl defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl andthe like; C₁₋₈alkyl encompasses the straight and branched chainedsaturated hydrocarbon radicals as defined in C₁₋₆alkyl as well as thehigher homologues thereof containing 7 or 8 carbon atoms such as, forexample heptyl or octyl; C₁₋₁₂alkyl again encompasses C₁₋₈alkyl and thehigher homologues thereof containing 9 to 12 carbon atoms, such as, forexample, nonyl, decyl, undecyl, dodecyl; C₁₋₁₆alkyl again encompassesC₁₋₁₂alkyl and the higher homologues thereof containing 13 to 16 carbonatoms, such as, for example, tridecyl, tetradecyl, pentedecyl andhexadecyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbonradicals containing one double bond and having from 2 to 6 carbon atomssuch as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl, and the like; C₁₋₆alkanediyl definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the branched isomers thereof. The term “C(═O)” refersto a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)₂” to asulfon. The term “natural amino acid” refers to a natural amino acidthat is bound via a covalent amide linkage formed by loss of a moleculeof water between the carboxyl group of the amino acid and the aminogroup of the remainder of the molecule. Examples of natural amino acidsare glycine, alanine, valine, leucine, isoleucine, methionine, proline,phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine,histidine.

The pharmaceutically acceptable acid or base addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid and non-toxic base addition salt forms which the compounds offormulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) areable to form. The compounds of formulas (I), (II), (III), (IV), (V),(VI), (VII), (VIII) or (IX) which have basic properties can be convertedin their pharmaceutically acceptable acid addition salts by treatingsaid base form with an appropriate acid. Appropriate acids comprise, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid),maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII),(VIII) or (IX) which have acidic properties may be converted in theirpharmaceutically acceptable base addition salts by treating said acidform with a suitable organic or inorganic base.

Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The terms acid or base addition salt also comprise the hydrates and thesolvent addition forms which the compounds of formulae (I), (II), (III),(IV), (V), (VI), (VII), (VIII) or (IX) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms of compounds of formulae (I),(II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), as usedhereinbefore, defines all possible compounds made up of the same atomsbonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII)or (IX) may possess. Unless otherwise mentioned or indicated, thechemical designation of a compound encompasses the mixture of allpossible stereochemically isomeric forms which said compound maypossess. Said mixture may contain all diastereomers and/or enantiomersof the basic molecular structure of said compound. All stereochemicallyisomeric forms of the compounds of formulae (I), (II), (III), (IV), (V),(VI), (VIII), (VIII) or (IX) both in pure form or in admixture with eachother are intended to be embraced within the scope of the presentinvention.

Some of the compounds of formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII) or (IX) may also exist in their tautomeric forms. Suchforms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formulae(I), (II),(III), (IV), (V), (VI), (VII), (VIII) or (IX)” is meant to include alsothe pharmaceutically acceptable acid or base addition salts and allstereoisomeric forms.

Other farnesyl protein transferase inhibitors which can be employed inaccordance with the present include Arglabin, perrilyl alcohol,SCH-66336,2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone (Merck); L778123, BMS 214662, Pfizer compounds A and B describedabove. These compounds can be prepared, for example, by methodsdescribed in the relevant patent specifications identified above whichare incorporated herein by reference.

Suitable dosages for the compounds Arglabin (WO98/28303), perrilylalcohol (WO 99/45712), SCH-66336 (U.S. Pat. No. 5,874,442), L778123 (WO00/01691),2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone (WO94/10138), BMS 214662 (WO 97/30992), Pfizer compounds A and B(WO 00/12499 and WO 00/12498) are given in the aforementioned patentspecifications which are incorporated herein by reference or are knownto or can be readily determined by a person skilled in the art.

In relation to perrilyl alcohol, the medicament may be administered 1-4gper day per 150 lb human patient. Preferably, 1-2 g per day per 150 lbhuman patient. SCH-66336 typically may be administered in a unit dose ofabout 0.1 mg to 100 mg, more preferably from about 1 mg to 300 mgaccording to the particular application. Compounds L778123 and1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinonemay be administered to a human patient in an amount between about 0.1mg/kg of body weight to about 20 mg/kg of body weight per day,preferably between 0.5 mg/kg of bodyweight to about 10 mg/kg of bodyweight per day.

Pfizer compounds A and B may be administered in dosages ranging fromabout 1.0 mg up to about 500 mg per day, preferably from about 1 toabout 100 mg per day in single or divided (i.e. multiple) doses.Therapeutic compounds will ordinarly be administered in daily dosagesranging from about 0.01 to about 10 mg per kg body weight per day, insingle or divided doses.

BMS 214662 may be administered in a dosage range of about 0.05 to 200mg/kg/day, preferably less than 100 mg/kg/day in a single dose or in 2to 4 divided doses.

This invention is especially applicable to the treatment of tumorsexpressing an activated ras oncogene. Examples of tumors which may beinhibited include, but are not limited to, lung cancer (e.g.adenocarcinoma and including non-small cell lung cancer), pancreaticcancers (e.g. pancreatic carcinoma such as, for example exocrinepancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, suchas, for example, colon adenocarcinoma and colon adenoma), hematopoietictumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-celllymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acutemyelogenous leukemia (AML)), thyroid follicular cancer, myelodysplasticsyndrome (MDS), tumors of mesenchymal origin (e.g. fibrosarcomas andrhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas,gliomas, benign tumor of the skin (e.g. keratoacanthomas), breastcarcinoma (e.g. advanced breast cancer), kidney carninoma, ovarycarcinoma, bladder carcinoma and epidermal carcinoma.

Farnesyl protein transferase inhibitors can be prepared and formulatedinto pharmaceutical compositions by methods known in the art and inparticular according to the methods described in the published patentspecifications, United States Patents, and United States PatentApplications, mentioned herein and incorporated by reference; for thecompounds of formulae (I), (II) and (III) suitable examples can be foundin WO-97/21701, and it's United States counterpart, U.S. Pat. No.6,037,350. Compounds of formulae (IV), (V), and (VI) can be prepared andformulated using methods described in WO 97/16443, and it's UnitedStates counterpart, U.S. Pat. No. 5,968,952; compounds of formulae (VII)and (VIII) according to methods described in WO 98/40383 and WO98/49157, and their United States counterparts, U.S. Pat. Nos. 6,187,786and 6,177,432, respectively; and compounds of formula (IX) according tomethods described in WO 00/39082, and it's United States counterpart,U.S. patent application Ser. No. 09/868,992. To prepare theaforementioned pharmaceutical compositions, a therapeutically effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for systemic administration such as oral,percutaneous, or parenteral administration; or topical administrationsuch as via inhalation, a nose spray, eye drops or via a cream, gel,shampoo or the like. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as glycols, oils, alcohols and the likein the case of oral liquid preparations such as suspensions, syrups,elixirs and solutions; or solid carriers such as starches, sugars,kaolin, lubricants, binders, disintegrating agents and the like in thecase of powders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable solutions containing compounds of formula (I) maybe formulated in an oil for prolonged action. Appropriate oils for thispurpose are, for example, peanut oil, sesame oil, cottonseed oil, cornoil, soy bean oil, synthetic glycerol esters of long chain fatty acidsand mixtures of these and other oils. Injectable suspensions may also beprepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wettable agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause any significant deleterious effects on theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on or as an ointment. As appropriate compositions fortopical application there may be cited all compositions usually employedfor topically administering drugs e.g. creams, gellies, dressings,shampoos, tinctures, pastes, ointments, salves, powders and the like.Application of said compositions may be by aerosol, e.g. with apropellent such as nitrogen, carbon dioxide, a freon, or without apropellent such as a pump spray, drops, lotions, or a semisolid such asa thickened composition which can be applied by a swab. In particular,semisolid compositions such as salves, creams, gellies, ointments andthe like will conveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The above farnesyl trasferase inhibitor may be used in combination withone or more other anti-cancer agents such as platinum coordinationcompounds for example cisplatin or carboplatin, taxane compounds forexample paclitaxel or docetaxel, camptothecin compounds for exampleirinotecan or topotecan, anti-tumor vinca alkaloids for examplevinblastine, vincristine or vinorelbine, anti-tumor nucleosidederivatives for example 5-fluorouracil, gemcitabine or capecitabine,nitrogen mustard or nitrosourea alkylating agents for examplecyclophosphamide, chlorambucil, carmustine or lomustine, anti-tumoranthracycline derivatives for example daunorubicin, doxorubicin,idarubicin or epirubicin; HER2 antibodies for example trastzumab;anti-tumor podophyllotoxin derivatives for example etoposide orteniposide; and antiestrogen agents including estrogen receptorantagonists or selective estrogen receptor modulators preferablytamoxifen, or alternatively toremifene, droloxifene, faslodex andraloxifene, or aromatase inhibitors such as exemestane, anastrozole,letrazole and vorozole.

The farnesyl transferase inhibitor and the further anti-cancer agent maybe administered simultaneously (e.g. in separate or unitarycompositions) or sequentially in either order. In the latter case, thetwo compounds will be administered within a period and in an amount andmanner that is sufficient to ensure that an advantageous or synergisticeffect is achieved. It will be appreciated that the preferred method andorder of administration and the respective dosage amounts and regimesfor each component of the combination will depend on the particularfarnesyl transferase inhibitor and further anti-cancer agents beingadministered, their route of administration, the particular tumor beingtreated and the particular host being treated. The optimum method andorder of administration and the dosage amounts and regime can be readilydetermined by those skilled in the art using conventional methods and inview of the information set out herein.

The FPT inhibitor for use in accordance with the present invention maybe prepared in a conventional manner, for example, by the processesdescribed in the above patent specifications

The following examples describe the invention in greater detail and areintended to illustrate but not to limit the invention.

EXAMPLE 1

Materials and Methods

Cell Culture: CAPAN-2 human pancreatic carcinoma cells were purchasedfrom the American Type Culture Collection (Rockville, Md.). Cells weremaintained in McCoys 5A Medium supplemented with 10% fetal calf serumand penicillin-streptomycin. NIH 3T3 cells transfected with theactivated T24 H-ras oncogene (T24 cells ) were obtained from, JanssenResearch Foundation (For methods see Parada, L. F., Tabin, C. J., Shih,C., and Weinberg, R Human EJ bladder carcinoma oncogene is

homologue of Harvey sarcoma virus ras gene. Nature 297: 474-478, 1982.;Santos, E., Tronick, S. R., Aaronson, S. A., Pulciani, S., and Barbacid,M. T24 human bladder carcinoma oncogene is an activated form of thenormal human homologue of BALB-and Harvey-MSV transforming genes. Nature298: 343-347, 1982.) T24 cells were maintained as monolayer cultures inDulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% Nu-serumType IV (Collaborative Biomedical Products, Bedford, Mass. and 40 μg/mlG418 (Geneticin®, GIBCO-BRL, Gaithersburg, Md.).

Animals: Female nu/nu immunodeficient nude mice (42 days old) werepurchased from Charles River Laboratories (Wilmington, Mass.). Mice werehoused five per cage in microisolator cages placed in laminar flowshelving to maintain sterility. All bedding, food, water and cages wereautoclaved. Animals were handled within the sterile confines of alaminar flow cabinet. The mice were otherwise maintained under standardvivarium conditions. Tumor studies were conducted under a protocolapproved by the Institutional Animal Care and Use Committee.

Tumor Studies In Nude Mice: Cells growing as monolayers in T150 tissueculture flasks were detached by trypsinization with 10 ml of 0.05%trypsin plus 0.53 mM EDTA per flask. Tumor cell suspensions were pooledand trypsin was inactivated by the addition of serum containing medium(10 ml per 40 ml of trypsin cell suspension). Cells were collected bycentrifugation and resuspended in Hank's Balanced Salt Solution (HBSS)warmed to 37° C. A 1.0 ml portion of cell suspension was added to 20 mlof diluent and counted on a Coulter particle counter. The cellsuspensions were recentrifuged and resuspended at a concentration of1×10⁶ cell per 0.10 ml of HBSS. Mice were inoculated with a singlesubcutaneous injection of 0.10 ml of tumor cell suspension in theinguinal region. Mice were housed five per cage with 15 mice assigned toeach treatment group. Body weight and tumor size as determined bycaliper measurements were measured weekly. The caliper measurements oflength and width were multiplied to obtain tumor areas. At the end ofstudy, mice were sacrificed by CO₂ asphyxiation.

Three days after tumor inoculation, the five day treatment with(R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(compound 1) was initiated. Compound 1 was administered once daily byoral gavage in a 20% beta-cyclodextrin vehicle as a volume of 0.10 ml ofsolution per 10 gm body weight. Control groups received the same dosagevolume of the 20% beta-cyclodextrin vehicle.

Compounds. Compound 1 was prepared for oral administration by dissolvingthe compound first as a 2× concentrated stock in 40% hydroxypropyl betacyclodextrin (lot no. 051-071/1) in 0.1 N HCI. Compound 1 was dissolvedby stirring vigorously approximately 30 minutes followed by sonicationfor 10 min. The compound 1 solutions were brought to a finalconcentration by diluting 1:1 with 0.1 N HCI. The final drug solutionswere sterile filtered immediately and transferred to sterile tubes.Solutions were stored refrigerated and protected form light during thecourse of the study and sterility was maintained by opening solutionsunder sterile laminar flow conditions.

Results and Discussion

Presented in FIG. 1 are the results of studying intermittent dosing ofcompound 1. Compound 1 was administered once daily for five days everythree weeks to nude mice bearing the T24 H-ras tumors. Vehicle treatedanimals presented with aggressively growing tumors 14 days afterinoculation. This group was sacrificed on day 17 since their tumorsexceeded the ethical guideline of a tumor burden no greater than 10%animal. body weight. Mice treated with 200 mg/kg compound I for fivedays (days 3-8 after tumor inoculation) presented with small tumors onday 17. Left untreated, the tumors returned to the rapid control growthrates by day 24. Animals were sacrificed on day 28 again according toethical guidelines. A separate group of 15 mice received an additional5-day treatment with 200 mg/kg compound 1. Tumor growth was againarrested but not as dramatically as in the initial treatment.

An identical dosing schedule was investigated in CAPAN-2 humanpancreatic tumors in nude mice. Administration of compound 1 for fivedays at a dose of 200 mg/kg significantly reduced the growth of CAPAN-2tumors out to day 24 (FIG. 2). Thereafter, tumors receiving no furthertreatment returned to the growth rate observed for vehicle treatedcontrols. Again, a separate group of 15 animals received an additionalfive-day treatment with compound 1 on days 21 to 25. Only, a transientgrowth arrest, which was significant on day 28 of study, was produced.Although the response of the CAPAN-2 tumors was not as dramatic as theT24 tumors, the present results are remarkable when compared to previousstudies. In our original evaluation of CAPAN-2 tumors with compound 1administered twice daily on a continuous schedule for 18 days, doses of50 mg/kg (100 mg/kg total daily dose) and 100 mg/kg (200 mg/kg) dailydose produced significant reductions of tumor growth. The five-daydosing schedule was a marked reduction in drug exposure from thisprevious study. Yet, an antitumor effect was still maintained

The dose dependency of the abbreviated five-day dosing schedule wasexplored in T24 tumors at compound 1 doses of 50, 100 and 200 mg/kg. Theduration of response was dose-related with the 200 mg dose againproducing sustained effects out to day 17 of study (FIG. 3). The tumorsuppressive effects of the lower doses waned by day 14. Significant,dose-related reductions of tumor growth measured as final tumor area(FIG. 4) and final tumor weights (FIG. 5) were still observed on day 17of study for all compound 1 treatment groups. The highest tested dose of200 mg/kg was substantially more effective than the lower does with a90% reduction of final tumor weights observed.

Finally, to address the minimum duration of FPT inhibitor exposurerequired to elicit an antitumor effect, animals were treated with asingle administration of compound 1. As shown in FIG. 6, a single 200mg/kg or 400 mg/kg dose of compound 1 given three days after tumorinoculation produced a sustained inhibition of tumor growth lasting outto 15 days.

The present studies demonstrate that abbreviated five-day exposures tocompound 1 can produce antitumor effects which persist for an additionaltwo weeks or greater beyond the treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Inhibition of the growth of T24 H-ras transformed NIH3T3 celltumors by compound 1 administered as five-day intermittent treatments.Nude mice were inoculated with 1×10⁶ T24 cells subcutaneously on day 0.After three days, oral dosing with beta-cyclodextrin vehicle (100 μl per10 gm body weight) or compound 1 (200 mg/kg) was initiated. Onetreatment group was treated for an additional five days starting on day21. Tumor size is expressed as tumor area (length×width). Values aremeans (±SEM) for N=14-15 animals per treatment group. For figureclarity, values significantly (p <0.05 by ANOVA) different from thevehicle treatment group are indicated (*) for day 21 only. Significanteffects for the second treatment cycle with compound 1 are indicated forday 28 (**).

FIG. 2. Inhibition of tumor growth in CAPAN-2 human pancreatic tumorsproduced by intermittent five day treatments with compound 1 (200 mg/kg,p.o.) Nude mice were inoculated with 1×10⁶ CAPAN-2 cells subcutaneously.After three days, oral dosing with beta-cyclodextrin vehicle (100 μl per10 gm body weight) or compound 1 (200 mg/kg) was initiated. Onetreatment group was treated for an additional five days starting on day21. Tumor size is expressed as tumor area (length×width). Values aremeans (±SEM) for N=14-15 animals per treatment group. For figureclarity, values significantly (p<0.05 by ANOVA) different from thevehicle treatment group are indicated (*) for day 24. Significanteffects for the second treatment cycle with compound 1 are indicated forday 28 (**).

FIG. 3. Time course for inhibition of the growth of T24 U-rastransformed NIH3T3 cell tumors by compound 1 administered as a singlefive-day treatment. Nude mice were inoculated with 1×10⁶ T24 cellssubcutaneously on day 0. After three days, daily oral dosing withbeta-cyclodextrin vehicle (100 μl per 10 gm body weight) or theindicated doses of compound 1 was initiated by oral gavage. Tumor sizeis expressed as tumor area (length×width). Values are means for N=14-15animals per treatment group. Statistical analyses for tumor measurementscollected at termination of study at day 17 are presented in FIGS. 4 and5.

FIG. 4. Inhibition of the growth of T24 H-ras transformed NIH3T3 celltumors by compound 1 administered as a single five-day treatment. Nudemice were inoculated with 1×10⁶ T24 cells subcutaneously on day 0. Afterthree days, oral dosing with beta-cyclodextrin vehicle (100 μl per 10 gmbody weight) or the indicated doses of compound 1 was initiated by oralgavage. Tumor size is expressed as tumor area (length x width). Valuesare means (±SEM) for N=14-15 animals per treatment group. Values withthe same letter are not significantly different (p<0.05 by ANOVA). Thepercent reduction in tumor size is presented over each histogram bar.

FIG. 5. Inhibition of the growth of T24 H-ras transformed NIH3T3 celltumors by compound 1 administered as a single five-day treatment. Nudemice were inoculated with 1×10⁶ T24 cells subcutaneously on day 0. Afterthree days, oral dosing with beta-cyclodextrin vehicle (100 μl per 10 gmbody weight) or the indicated doses of compound 1 was initiated by oralgavage. Tumor size is expressed as post mortem tumor weight (g). Valuesare means (±SEM) for N=14-15 animals per treatment group. Values withthe same letter are not significantly different (p<0.05 by ANOVA). Thepercent reduction in tumor weight is indicated over each histogram bar.

FIG. 6. Time course for inhibition of the growth of T24 H-rastransformed NIH3T3 cell tumors by compound 1 administered as asingle-treatment. Nude mice were inoculated with 1×10⁶ T24 cellssubcutaneously on day 0. After three days, daily oral dosing withbeta-cyclodextrin vehicle (100 μl per 10 gm body weight) or theindicated doses of compound 1 was initiated by oral gavage. Tumor sizeis expressed as tumor area (length x width). Values are means forN=14-15 animals per treatment group.

1. A method for the treatment of cancer in mammals which comprisesadministering a farnesyl protein transferase inhibitor once daily over aperiod of one to five days, followed by a period of at least fourteendays during which period no farnesyl transferase inhibitor isadministered, the said farnesyl transferase inhibitor being a compoundof formula (I):

a stereoisomeric form thereof, a pharmaceutically acceptable acid orbase addition salt thereof, wherein the dotted line represents anoptional bond; X is oxygen or sulfur; R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹,Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl, pyridyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or—Alk¹—S(O)2—R⁹, wherein Alk¹ is C₁₋₆alkanediyl, R⁹ is hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylaminosubstituted with C₁₋₆alkyloxycarbonyl; R², R³ and R¹⁶ each independentlyare hydrogen, hydroxy, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar₁, AR²C₁₋₆alkyl, AR²oxy,AR²C₁₋₆alkyloxy, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, trihalomethyl,trihalomethoxy, C₂₋₆alkenyl, 4,4-dimethyloxazolyl; or when on adjacentpositions R²and R³ taken together may form a bivalent radical of formula—O—CH₂—O—  (a-1)—O—CH₂—CH₂—O—  (a-2)—O—CH═CH—  (a-3)—O—CH₂—CH₂—  (a-4)—O—CH₂—CH₂—CH₂—  (a-5) or—CH═CH—CH═CH—  (a-6) R⁴ and R⁵ each independently are hydrogen, halo,Ar¹, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylthio, amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylS(O)C₁₋₆alkyl or C₁₋₆alkylS(O)₂C₁₋₆alkyl; R⁶ and R⁷ eachindependently are hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy,Ar²oxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, or when onadjacent positions R⁶ and R⁷ taken together may form a bivalent radicalof formula—O—CH₂—O—  (c-1) or—CH═CH—CH═CH—  (c-2) R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula—O—R¹⁰  (b-1),—S—R¹⁻  )b-2),—N—R¹¹R¹²  (b-3), wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,Ar¹, Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R^(15;) R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ orAr²C₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, C₁₋₁₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, a natural amino acid, Ar¹ carbonyl,Ar²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical of formula —Alk²—OR¹³ or—Alk²—NR¹⁴R¹⁵; wherein Alk² is C₁₋₆alkanediyl;  R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;  R¹⁵ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar²C₁₋₆alkyl; R¹⁷ is hydrogen,halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹; R¹⁸ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy or halo; R¹⁹ is hydrogen or C₁₋₆alkyl; Ar¹ isphenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and Ar² is phenyl or phenyl substituted withC₁₋₆alkyl, hydroxy, amino, C₁₋₆alkyloxy or halo, wherein said cancer issensitive the effects of said farnesyl transferase inhibitor.
 2. Themethod of claim 1 wherein the farnesyl protein transferase inhibitor isadministered at a dose of 50-1200, mg/kg body weight.
 3. The method ofclaim 1 wherein the farnesyl protein transferase inhibitor isadministered at a dose of 50-400, mg/kg body weight.
 4. The method ofclaim 1 wherein the farnesyl protein transferase inhibitor isadministered at a dose of 50-200, mg/kg body weight.
 5. The method ofclaim 1 wherein the farnesyl protein transferase inhibitor isadministered for one day.
 6. The method of claim 1 wherein the farnesylprotein transferase inhibitor is administered for five days.
 7. Themethod of claim 1 wherein said farnesyl protein transferase inhibitor isa compound of formula (I) wherein X is oxygen and the dotted linerepresents a bond.
 8. The method of claim 1 wherein said farnesylprotein transferase inhibitor is a compound of formula (I) wherein R¹ ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl or, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl; R² is halo, C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₆alkyloxy, trihalomethoxy, or hydroxyC₁₋₆alkyloxy; and R³ ishydrogen.
 9. The method of claim 1 wherein R⁸ is hydrogen, hydroxy,haloC¹⁻⁶alkyl, hydroxyC¹⁻⁶alkyl, cyanoC¹⁻⁶alkyl,C¹⁻⁶alkyloxycarbonylC¹⁻⁶alkyl, imidazolyl, or a radical of formula—NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, or aradical of formula —Alk²—OR¹³ wherein R¹³ is hydrogen or C₁₋₆alkyl. 10.The method of claim 1 wherein the farnesyl protein transferase inhibitoris(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid addition salt thereof.